Burnout and Self Care for Palliative Care Practitioners.

Burnout is common in physicians who care for patients with serious illness, with rates greater than 60% in some studies. Risk factors for burnout include working on small teams and/or in small organizations, working longer hours and weekends, being younger than 50 years, burdensome documentation requirements, and regulatory issues. Personal factors that can protect against burnout include mindfulness, exercise, healthy sleep patterns, avoiding substance abuse, and having adequate leisure time. Institutional and work factors that can buffer against burnout include working on adequately staffed teams, having a manageable workload, and minimally burdensome electronic health record documentation.

Setting Our Sights on Infectious Diseases.

In May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery, translational, and clinical development processes. We started with an introductory session on the current situation and then worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies, drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learnings.

Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition.

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the ß5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the ß4 and ß5 proteasome subunits. This induced pocket exploits ß4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.

Effects of age and hearing mechanism on spectral resolution in normal hearing and cochlear-implanted listeners.

Spectral resolution limits speech perception with a cochlear implant (CI) in post-lingually deaf adults. However, the development of spectral resolution in pre-lingually deaf implanted children is not well understood. Acoustic spectral resolution was measured as a function of age (school-age versus adult) in CI and normal-hearing (NH) participants using spectral ripple discrimination (SRD). A 3-alternative forced-choice task was used to obtain SRD thresholds at five ripple depths. Effects of age and hearing method on SRD and spectral modulation transfer function (SMTF) slope (reflecting frequency resolution) and x-intercept (reflecting across-channel intensity resolution) were examined. Correlations between SRD, SMTF parameters, age, and speech perception in noise were studied. Better SRD in NH than CI participants was observed at all depths. SRD thresholds and SMTF slope correlated with speech perception in CI users. When adjusted for floor performance, x-intercept did not correlate with SMTF slope or speech perception. Age and x-intercept correlations were positive and significant in NH but not CI children suggesting that across-channel intensity resolution matures during school-age in NH children. No evidence for maturation of spectral resolution beyond early school-age in pre-lingually deaf implanted CI users was found in the present study.

Advancing the Food-Energy-Water Nexus: Closing Nutrient Loops in Arid River Corridors.

Closing nutrient loops in terrestrial and aquatic ecosystems is integral to achieve resource security in the food-energy-water (FEW) nexus. We performed multiyear (2005-2008), monthly sampling of instream dissolved inorganic nutrient concentrations (NH4-N, NO3-N, soluble reactive phosphorus-SRP) along a ∼ 300-km arid-land river (Rio Grande, NM) and generated nutrient budgets to investigate how the net source/sink behavior of wastewater and irrigated agriculture can be holistically managed to improve water quality and close nutrient loops. Treated wastewater on average contributed over 90% of the instream dissolved inorganic nutrients (101 kg/day NH4-N, 1097 kg/day NO3-N, 656 kg/day SRP). During growing seasons, the irrigation network downstream of wastewater outfalls retained on average 37% of NO3-N and 45% of SRP inputs, with maximum retention exceeding 60% and 80% of NO3-N and SRP inputs, respectively. Accurate quantification of NH4-N retention was hindered by low loading and high variability. Nutrient retention in the irrigation network and instream processes together limited downstream export during growing seasons, with total retention of 33-99% of NO3-N inputs and 45-99% of SRP inputs. From our synoptic analysis, we identify trade-offs associated with wastewater reuse for agriculture within the scope of the FEW nexus and propose strategies for closing nutrient loops in arid-land rivers.

Nutrient treatments alter microbial mat colonization in two glacial meltwater streams from the McMurdo Dry Valleys, Antarctica.

Microbial mats are abundant in many alpine and polar aquatic ecosystems. With warmer temperatures, new hydrologic pathways are developing in these regions and increasing dissolved nutrient fluxes. In the McMurdo Dry Valleys, thermokarsting may release both nutrients and sediment, and has the potential to influence mats in glacial meltwater streams. To test the role of nutrient inputs on community structure, we created nutrient diffusing substrata (NDS) with agar enriched in N, P and N + P, with controls, and deployed them into two Dry Valley streams. We found N amendments (N and N + P) to have greater chlorophyll-a concentrations, total algal biovolume, more fine filamentous cyanobacteria and a higher proportion of live diatoms than other treatments. Furthermore, N treatments were substantially elevated in Bacteroidetes and the small diatom, Fistulifera pelliculosa. On the other hand, species richness was almost double in P and N + P treatments over others, and coccoid green algae and Proteobacteria were more abundant in both streams. Collectively, these data suggest that nutrients have the potential to stimulate growth and alter community structure in glacial meltwater stream microbial mats, and the recent erosion of permafrost and accelerated glacial melt will likely impact resident biota in polar lotic systems here and elsewhere.

Non-clinical safety studies of IMT504, a unique non-CpG oligonucleotide.

IMT504 is a non-CpG 24-mer oligodeoxynucleotide (ODN) with immunomodulatory as well as tissue repair activity. IMT504 has been previously proven to be effective in animal models of vaccine potency, chronic lymphocytic leukemia, tissue regeneration, and sepsis. Here, we assessed the safety, including pharmacokinetics and toxicity studies in rats and monkeys, of IMT504 in a single- or repeated-dose administration by the subcutaneous (SC) or intravenous (IV) routes. In rats, the maximum tolerated dose was determined to be 50 mg/kg when administered SC. Adverse effects at 50 mg/kg were mild and reversible liver injury, revealed as lobular inflammation, focal necrosis, and small changes in the transaminase profile. Dose-dependent splenomegaly and lymphoid hyperplasia, most probably associated with immune stimulation, were commonly observed. Rats and monkeys were also IV injected with a single dose of 10 or 3.5 mg/kg, and no adverse effects were observed. Rats injected IV with 10 mg/kg showed a transient increase in spleen weight, together with a slight increase in the marginal zone of the white pulp and in leukocyte count 2 days post-administration. In monkeys, this dosage caused slight changes in total serum complement and leukocyte count on day 14. No adverse effects were observed at 3.5 mg/kg IV in rats or monkeys. Therefore, this dose was defined as the "no observed adverse effect level" for this route. Furthermore, repeated-dose toxicity studies were performed in these species using 3.5 or 0.35 mg/kg/day IV for 6 weeks. A transient increase in the spleen and liver weight was observed at 3.5 mg/kg/day only in female rats. No changes in clotting time and activation of the alternative complement pathway were observed. The toxicity profile of IMT504 herein reported suggests a dose range in which IMT504 can be used safely in clinical trials.

Common peptides study of aminoacyl-tRNA synthetases.

BACKGROUND: Aminoacyl tRNA synthetases (aaRSs) constitute an essential enzyme super-family, providing fidelity of the translation process of mRNA to proteins in living cells. They are common to all kingdoms and are of utmost importance to all organisms. It is thus of great interest to understand the evolutionary relationships among them and underline signature motifs defining their common domains. RESULTS: We utilized the Common Peptides (CPs) framework, based on extracted deterministic motifs from all aaRSs, to study family-specific properties. We identified novel aaRS-class related signatures that may supplement the current classification methods and provide a basis for identifying functional regions specific to each aaRS class. We exploited the space spanned by the CPs in order to identify similarities between aaRS families that are not observed using sequence alignment methods, identifying different inter-aaRS associations across different kingdom of life. We explored the evolutionary history of the aaRS families and evolutionary origins of the mitochondrial aaRSs. Lastly, we showed that prevalent CPs significantly overlap known catalytic and binding sites, suggesting that they have meaningful functional roles, as well as identifying a motif shared between aaRSs and a the Biotin-[acetyl-CoA carboxylase] synthetase (birA) enzyme overlapping binding sites in both families. CONCLUSIONS: The study presents the multitude of ways to exploit the CP framework in order to extract meaningful patterns from the aaRS super-family. Specific CPs, discovered in this study, may play important roles in the functionality of these enzymes. We explored the evolutionary patterns in each aaRS family and tracked remote evolutionary links between these families.

Dynamic range enhancement for cochlear implants.

HYPOTHESIS: The addition of a continuous, unmodulated, high-rate pulse train to sinusoidal stimuli presented by the cochlear implant to implant recipients will result in increases in the psychophysical dynamic range. BACKGROUND: The hearing dynamic range of cochlear implant patients is markedly reduced compared with that of normal-hearing individuals. This has negative implications for both speech perception and sound quality in these patients. It has been suggested that the addition of an unmodulated high-rate pulse train to deafened auditory nerves could create spontaneous-like neural activity, similar to that recorded from normal ears, of which one significant benefit would be an increase in the dynamic range of cochlear implant users. METHODS: Twenty-nine patients who underwent implantation with the Clarion CII device participated in this single-blinded prospective study. The psychophysical dynamic range of 28 of these subjects was measured with sinusoidal stimuli in response to various levels of an additional unmodulated high-rate pulse train. RESULTS: All the tested subjects (n = 28) demonstrated an increase in dynamic range in response to an appropriate level of unmodulated high-rate pulse train. The largest increase in dynamic range for each subject had a mean value of 6.7 dB. CONCLUSION: The addition of an unmodulated high-rate pulse train to the electric signal presented to cochlear implant patients results in significant increases in dynamic range for sinusoidal stimuli.